The etiology of BPH remains obscure. Although aging and the presence of testes are permissive, these factors are not sufficient for the pathogenesis of clinical BPH. Autopsy studies have demonstrated that histologic BPH prevalence approaches 90% by age 80, but it is unclear at what point within this continuum and under what influence, microscopic evidence of hyperplasia becomes a clinically pathologic entity. There have been no large longitudinal cohort studies in humans that have used objective criteria to evaluate aging men with and without prostatic enlargement to gain insight into the pathogenesis, pathophysiology, and natural history of BPH. Elucidation of the pathogenesis of human BPH can identify potential new avenues of therapy and intervention. We propose to characterize dynamic aspects of BPH pathogenesis in a longitudinal study of prostate aging, to develop non-invasive techniques of assessing stromal and epithelial changes seen in BPH pathogenesis, and, expanding upon recent work demonstrating a genetic form of BPH, to conduct clinical genetic studies to identify genes involved in the pathogenesis of BPH. Longitudinal development of BPH will be evaluated in men participating in the Baltimore Longitudinal Study of Aging. Changes in prostate size, stromal epithelial ratio, serum PSA, and serum hormone profiles will be evaluated and their association with obstructive symptoms and response to therapy will be assessed. This study will build on preliminary data suggesting that PSA secretion by BPH tissue has unique characteristics, and will utilize a well established cohort of aging men. Recently developed MRI techniques capable of distinguishing between stromal and epithelial hyperplasia will be validated, optimized, and applied to the longitudinal aging cohort as well as to other men with clinical BPH in an attempt to prospectively determine predictors of clinical course. Epidemiological genetic studies will be undertaken in a national cohort of 4000 men with BPH and in a cohort of 10000 aging twins to confirm preliminary findings which identified a hereditary form of BPH. The potential role of hormonal factors in men with familial BPH will be evaluated, and linkage analysis will be initiated to identify genetic loci involved in familial BPH clustering. These studies aim to identify specific factors involved in the pathogenesis of human BPH and thereby identify potential new rational strategies of prevention and therapy.